Tenofovir Disoproxil Fumarate (TDF) is a water soluble anti-HIV and anti-HBV oral drug, stable in the stomach, enters the body with the blood after the intestinal absorption, and uniformly distributed within human tissues; less than 20% is metabolized and activated into the Tenofovir parent drug under the action of esterase, and then diphosphorylated into Tenofovir diphosphate to take effect, and about the remaining 80% is excreted out of the body in original form. To improve the bio-availability, currently, the strategy of introducing the masking group onto the phosphate group of the Tenofovir to form the lipid soluble pro-drug is usually adopted. Structurally, one masking group is linked with the phosphate group to form a phosphoramide structure, another group linked with the phosphate group to form a phospholipid structure. The compound with this structure is proven to have the lymph and liver tissue targeting effect. Ester-forming groups include various aromatic rings and heteroaromatic rings, especially the substituted or unsubstituted phenyl (CN201310041647.4, WO 200208241 A2). The patent (CN01813161) disclosed a compound GS-7340 obtained by using such pro-drug strategy, which enhanced the liver-targeting properties compared with Tenofovir Disoproxil Fumarate (TDF), while the efficacy enhanced and the toxicity reduced. However, due to the unstability of the phenol group acting as the masking group, metabolism may still occur in the blood to produce the active parent drug Tenofovir, and therefore brings certain systemic toxicity. The phenol produced by the metabolism also has relatively high toxicity itself. The benzyl type Tenofovir pro-drug compound with substitution(s) on the benzene ring has been proven to have liver-targeting activities. Patents US20130210757 and CN201380030061.6 disclosed that one masking group was phosphoramide formed by the amino acid ester and the phosphate group; another masking group was benzyl ester with substitution(s) on the benzene ring formed by benzyl with the electron-donating groups such as methyl on the benzene ring at the ortho or para position, and the phosphate group. However, there's no report of the synthesis and bio-activity researches for the Tenofovir pro-drug compound by using the unsubstituted benzyl as an ester-forming group, in part because the benzyl group without substitution(s) on the benzene ring can not be metabolized during the use of the 5-fluorouracil nucleotide pro-drug, causing it to be not active (WO 200208241 A2).
The masking group of o-methyl benzyl of the compound structure disclosed in CN201380030061.6 has a high group-leaving activity and low stability during the blood esterase metabolism, the targeting group is relatively easier to be detached, therefore leading to the relative increase of the active parent drug in the blood and relative decrease of the active parent drug in the liver, and affecting the activity and systemic toxicity.

To enhance the bio-activity of Tenofovir and upgrade its anti-virus activity, the present invention provides a class of tenofovir monobenzyl ester phosphamide compounds without substitution(s) on the benzene ring of the benzyl group, and the preparation method thereof, as well as their use in the lymph-targeting anti-AIDS infection and the liver-targeting anti-hepatitis B treatment; compared with GS-7340 and compound 7, such pro-drugs are more stable against esterase, and further enhance the systemic stability and liver-targeting anti-virus effect of the Tenofovir analogs.